ES2841324T3 - Proceso para la 6,7-alfa-epoxidación de 4,6-dienos esteroideos - Google Patents

Proceso para la 6,7-alfa-epoxidación de 4,6-dienos esteroideos Download PDF

Info

Publication number: ES2841324T3
Authority: ES; Spain
Prior art keywords: general formula; alkyl; group; halo; compound
Prior art date: 2016-05-18
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Active

Application number

ES17725742T

Other languages

English (en)

Spanish (es)

Inventor

Alexander Charles Weymouth-Wilson

Zofia Komsta

Laura Wallis

Timothy Evans

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Nzp Uk Ltd

Original Assignee

Nzp Uk Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2016-05-18

Filing date

2017-05-18

Publication date

2021-07-08

2017-05-18 Application filed by Nzp Uk Ltd filed Critical Nzp Uk Ltd

2021-07-08 Application granted granted Critical

2021-07-08 Publication of ES2841324T3 publication Critical patent/ES2841324T3/es

Status Active legal-status Critical Current

2037-05-18 Anticipated expiration legal-status Critical

Links

238000000034 method Methods 0.000 title claims abstract description 126
230000008569 process Effects 0.000 title claims abstract description 68
238000006735 epoxidation reaction Methods 0.000 title description 53
230000003637 steroidlike Effects 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 560
-1 C (O) Ph Chemical group 0.000 claims abstract description 84
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 74
125000001424 substituent group Chemical group 0.000 claims abstract description 71
125000003118 aryl group Chemical group 0.000 claims abstract description 57
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 44
125000000217 alkyl group Chemical group 0.000 claims abstract description 43
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims abstract description 42
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 40
229910052799 carbon Inorganic materials 0.000 claims abstract description 39
150000003839 salts Chemical class 0.000 claims abstract description 39
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 38
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 37
239000007800 oxidant agent Substances 0.000 claims abstract description 33
238000007254 oxidation reaction Methods 0.000 claims abstract description 33
125000004429 atom Chemical group 0.000 claims abstract description 32
230000003647 oxidation Effects 0.000 claims abstract description 31
125000002947 alkylene group Chemical group 0.000 claims abstract description 30
230000001590 oxidative effect Effects 0.000 claims abstract description 29
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims abstract description 27
239000003054 catalyst Substances 0.000 claims abstract description 26
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 26
125000004450 alkenylene group Chemical group 0.000 claims abstract description 25
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 24
239000001257 hydrogen Substances 0.000 claims abstract description 24
101000927076 Xenopus laevis Apoptosis regulator R11 Proteins 0.000 claims abstract description 23
230000000155 isotopic effect Effects 0.000 claims abstract description 23
150000003536 tetrazoles Chemical class 0.000 claims abstract description 23
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 22
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 22
150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 20
125000005647 linker group Chemical group 0.000 claims abstract description 18
229920001223 polyethylene glycol Polymers 0.000 claims abstract description 18
239000002202 Polyethylene glycol Substances 0.000 claims abstract description 17
125000004419 alkynylene group Chemical group 0.000 claims abstract description 15
150000001540 azides Chemical class 0.000 claims abstract description 14
125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims abstract description 12
229910052760 oxygen Inorganic materials 0.000 claims abstract description 12
125000003837 (C1-C20) alkyl group Chemical group 0.000 claims abstract description 11
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 11
125000003358 C2-C20 alkenyl group Chemical group 0.000 claims abstract description 11
238000004519 manufacturing process Methods 0.000 claims abstract description 10
229910052717 sulfur Inorganic materials 0.000 claims abstract description 10
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 9
125000003827 glycol group Chemical group 0.000 claims abstract description 9
125000001188 haloalkyl group Chemical group 0.000 claims abstract description 9
XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims abstract description 9
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 5
238000006243 chemical reaction Methods 0.000 claims description 205
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 177
239000000203 mixture Substances 0.000 claims description 88
235000019439 ethyl acetate Nutrition 0.000 claims description 83
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 69
239000002904 solvent Substances 0.000 claims description 49
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
125000006239 protecting group Chemical group 0.000 claims description 22
AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 claims description 22
XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 claims description 21
125000000304 alkynyl group Chemical group 0.000 claims description 21
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 17
239000007810 chemical reaction solvent Substances 0.000 claims description 15
239000003446 ligand Substances 0.000 claims description 14
230000009467 reduction Effects 0.000 claims description 13
239000003153 chemical reaction reagent Substances 0.000 claims description 12
239000003638 chemical reducing agent Substances 0.000 claims description 12
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 11
125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 11
DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 10
125000002524 organometallic group Chemical group 0.000 claims description 8
RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 7
238000002360 preparation method Methods 0.000 claims description 7
BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical group FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 6
ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 6
125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 6
230000029936 alkylation Effects 0.000 claims description 6
238000005804 alkylation reaction Methods 0.000 claims description 6
238000006345 epimerization reaction Methods 0.000 claims description 6
UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 6
GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
ZQBFAOFFOQMSGJ-UHFFFAOYSA-N hexafluorobenzene Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1F ZQBFAOFFOQMSGJ-UHFFFAOYSA-N 0.000 claims description 4
125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 3
125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims description 3
GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 claims description 3
YIHRGKXNJGKSOT-UHFFFAOYSA-N 1,1,2,2,3,3-hexafluorobutan-1-ol Chemical compound CC(F)(F)C(F)(F)C(O)(F)F YIHRGKXNJGKSOT-UHFFFAOYSA-N 0.000 claims description 2
239000002879 Lewis base Substances 0.000 claims description 2
VTIIJXUACCWYHX-UHFFFAOYSA-L disodium;carboxylatooxy carbonate Chemical compound [Na+].[Na+].[O-]C(=O)OOC([O-])=O VTIIJXUACCWYHX-UHFFFAOYSA-L 0.000 claims description 2
150000007527 lewis bases Chemical class 0.000 claims description 2
229940045872 sodium percarbonate Drugs 0.000 claims description 2
125000001475 halogen functional group Chemical group 0.000 claims 27
125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims 1
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
125000005843 halogen group Chemical group 0.000 abstract description 80
239000007787 solid Substances 0.000 description 77
239000000243 solution Substances 0.000 description 76
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 72
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 71
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
230000015572 biosynthetic process Effects 0.000 description 66
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 63
238000003786 synthesis reaction Methods 0.000 description 63
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 56
239000002253 acid Substances 0.000 description 55
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 54
239000000047 product Substances 0.000 description 52
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 50
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 47
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
239000011541 reaction mixture Substances 0.000 description 38
239000012074 organic phase Substances 0.000 description 37
230000002829 reductive effect Effects 0.000 description 36
125000004494 ethyl ester group Chemical group 0.000 description 34
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 29
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 28
ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
239000011780 sodium chloride Substances 0.000 description 27
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
239000010410 layer Substances 0.000 description 24
238000010898 silica gel chromatography Methods 0.000 description 24
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 23
238000007792 addition Methods 0.000 description 23
239000007858 starting material Substances 0.000 description 22
238000005160 1H NMR spectroscopy Methods 0.000 description 21
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
239000002585 base Substances 0.000 description 21
OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 20
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
239000008346 aqueous phase Substances 0.000 description 20
229910052938 sodium sulfate Inorganic materials 0.000 description 20
235000011152 sodium sulphate Nutrition 0.000 description 20
OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 19
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
235000017557 sodium bicarbonate Nutrition 0.000 description 19
229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
239000000706 filtrate Substances 0.000 description 18
HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 17
238000003756 stirring Methods 0.000 description 17
238000004809 thin layer chromatography Methods 0.000 description 17
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 16
LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 16
235000016831 stigmasterol Nutrition 0.000 description 16
229940032091 stigmasterol Drugs 0.000 description 16
BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 16
239000000725 suspension Substances 0.000 description 16
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
239000003613 bile acid Substances 0.000 description 15
ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 15
229960001601 obeticholic acid Drugs 0.000 description 15
125000004432 carbon atom Chemical group C* 0.000 description 14
239000012065 filter cake Substances 0.000 description 14
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 13
229910052786 argon Inorganic materials 0.000 description 13
239000000284 extract Substances 0.000 description 13
238000001914 filtration Methods 0.000 description 13
150000002924 oxiranes Chemical class 0.000 description 13
125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
125000003342 alkenyl group Chemical group 0.000 description 12
235000019270 ammonium chloride Nutrition 0.000 description 12
KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 12
238000004128 high performance liquid chromatography Methods 0.000 description 12
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
239000000543 intermediate Substances 0.000 description 12
FODOUIXGKGNSMR-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate;hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O FODOUIXGKGNSMR-UHFFFAOYSA-L 0.000 description 12
239000003960 organic solvent Substances 0.000 description 12
ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 12
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 12
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
239000012071 phase Substances 0.000 description 11
238000006722 reduction reaction Methods 0.000 description 11
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 11
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 10
150000002148 esters Chemical class 0.000 description 10
OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 10
229910052763 palladium Inorganic materials 0.000 description 10
238000000746 purification Methods 0.000 description 10
102100038495 Bile acid receptor Human genes 0.000 description 9
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 9
101000603876 Homo sapiens Bile acid receptor Proteins 0.000 description 9
DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 9
229910052794 bromium Inorganic materials 0.000 description 9
150000002430 hydrocarbons Chemical group 0.000 description 9
239000003921 oil Substances 0.000 description 9
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 9
RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 8
DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 8
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
230000002378 acidificating effect Effects 0.000 description 8
WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 description 8
NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 8
238000006772 olefination reaction Methods 0.000 description 8
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150000002825 nitriles Chemical class 0.000 description 1
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238000005191 phase separation Methods 0.000 description 1
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238000006116 polymerization reaction Methods 0.000 description 1
229920005862 polyol Polymers 0.000 description 1
150000003077 polyols Chemical class 0.000 description 1
FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
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230000001681 protective effect Effects 0.000 description 1
150000003222 pyridines Chemical class 0.000 description 1
LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
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SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
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CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
235000010288 sodium nitrite Nutrition 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
241000894007 species Species 0.000 description 1
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230000000707 stereoselective effect Effects 0.000 description 1
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125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
150000003461 sulfonyl halides Chemical class 0.000 description 1
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
230000001629 suppression Effects 0.000 description 1
229960003080 taurine Drugs 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
125000003831 tetrazolyl group Chemical group 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
JKVRTUCVPZTEQZ-UHFFFAOYSA-N tributyltin azide Chemical compound CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-] JKVRTUCVPZTEQZ-UHFFFAOYSA-N 0.000 description 1
GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
JGWFUSVYECJQDT-UHFFFAOYSA-N trimethyl(2-trimethylsilyloxyethoxy)silane Chemical compound C[Si](C)(C)OCCO[Si](C)(C)C JGWFUSVYECJQDT-UHFFFAOYSA-N 0.000 description 1
SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
IBYSTTGVDIFUAY-UHFFFAOYSA-N vanadium monoxide Chemical compound [V]=O IBYSTTGVDIFUAY-UHFFFAOYSA-N 0.000 description 1
MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
235000012141 vanillin Nutrition 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
239000002699 waste material Substances 0.000 description 1
239000011701 zinc Substances 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Toxicology (AREA)
Steroid Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

ES17725742T 2016-05-18 2017-05-18 Proceso para la 6,7-alfa-epoxidación de 4,6-dienos esteroideos Active ES2841324T3 (es)

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GBGB1608776.9A GB201608776D0 (en)	2016-05-18	2016-05-18	Methods and compounds
PCT/GB2017/051389 WO2017199036A1 (fr)	2016-05-18	2017-05-18	Procédé et intermédiaires pour l'époxydation 6,7-alpha de 4,6-diènes stéroïdes

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US (1)	US10766921B2 (fr)
EP (1)	EP3458467B1 (fr)
JP (1)	JP7034094B2 (fr)
KR (1)	KR102489565B1 (fr)
CN (1)	CN109415404B (fr)
AU (1)	AU2017265445B2 (fr)
CA (1)	CA3024283A1 (fr)
DK (1)	DK3458467T3 (fr)
EA (1)	EA038224B1 (fr)
ES (1)	ES2841324T3 (fr)
GB (1)	GB201608776D0 (fr)
MX (1)	MX378594B (fr)
PT (1)	PT3458467T (fr)
WO (1)	WO2017199036A1 (fr)

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GB201608776D0 (en)	2016-05-18	2016-06-29	Dextra Lab Ltd	Methods and compounds
GB201608777D0 (en)	2016-05-18	2016-06-29	Dextra Lab Ltd	Compounds
GB201812382D0 (en)	2018-07-30	2018-09-12	Nzp Uk Ltd	Compounds
CN111560045A (zh) *	2020-06-23	2020-08-21	江苏佳尔科药业集团股份有限公司	一种以ba为原料合成石胆酸的方法
CN114957368B (zh) *	2021-09-08	2024-07-26	湖南科益新生物医药有限公司	中间体化合物及其制备方法和应用
CN114957372B (zh) *	2021-12-07	2023-10-31	湖南醇康医药科技有限公司	10α-甲基-5,7-二烯甾体化合物和地屈孕酮的制备方法

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DE3902357A1 (de)	1989-01-27	1990-08-02	Hoechst Ag	Verwendung von rheniumorganischen verbindungen zur oxidation von c-c-mehrfachbindungen, darauf basierende oxidationsverfahren und neue rheniumorganische verbindungen
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CA2118130A1 (fr)	1992-04-14	1993-10-28	Jean M. J. Frechet	Macromolecules composees de polymeres dendritiques et methode de production
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2016
- 2016-05-18 GB GBGB1608776.9A patent/GB201608776D0/en not_active Ceased
2017
- 2017-05-18 CA CA3024283A patent/CA3024283A1/fr active Pending
- 2017-05-18 DK DK17725742.5T patent/DK3458467T3/da active
- 2017-05-18 EP EP17725742.5A patent/EP3458467B1/fr active Active
- 2017-05-18 EA EA201892516A patent/EA038224B1/ru unknown
- 2017-05-18 KR KR1020187035835A patent/KR102489565B1/ko active Active
- 2017-05-18 WO PCT/GB2017/051389 patent/WO2017199036A1/fr not_active Ceased
- 2017-05-18 PT PT177257425T patent/PT3458467T/pt unknown
- 2017-05-18 US US16/302,057 patent/US10766921B2/en active Active
- 2017-05-18 AU AU2017265445A patent/AU2017265445B2/en active Active
- 2017-05-18 MX MX2018014130A patent/MX378594B/es unknown
- 2017-05-18 JP JP2018560672A patent/JP7034094B2/ja active Active
- 2017-05-18 CN CN201780030784.4A patent/CN109415404B/zh active Active
- 2017-05-18 ES ES17725742T patent/ES2841324T3/es active Active

Also Published As

Publication number	Publication date
CN109415404A (zh)	2019-03-01
PT3458467T (pt)	2021-01-05
CA3024283A1 (fr)	2017-11-23
KR20190007011A (ko)	2019-01-21
EA201892516A1 (ru)	2019-05-31
US10766921B2 (en)	2020-09-08
BR112018073492A2 (pt)	2019-03-26
EA038224B1 (ru)	2021-07-27
AU2017265445B2 (en)	2020-12-03
DK3458467T3 (da)	2020-12-14
US20190309012A1 (en)	2019-10-10
JP7034094B2 (ja)	2022-03-11
KR102489565B1 (ko)	2023-01-17
AU2017265445A1 (en)	2018-11-15
CN109415404B (zh)	2022-08-26
MX378594B (es)	2025-03-11
WO2017199036A1 (fr)	2017-11-23
EP3458467B1 (fr)	2020-09-30
EP3458467A1 (fr)	2019-03-27
MX2018014130A (es)	2019-04-29
GB201608776D0 (en)	2016-06-29
JP2019516729A (ja)	2019-06-20

Publication	Publication Date	Title
ES2841324T3 (es)	2021-07-08	Proceso para la 6,7-alfa-epoxidación de 4,6-dienos esteroideos
ES2857869T3 (es)	2021-09-29	6,7-beta-epóxidos de esteroides como compuestos intermedios químicos
KR102526631B1 (ko)	2023-04-27	스테로이드 fxr 조절인자를 제조하기 위한 중간체로서의 6-알킬-7-하이드록시-4-엔-3-온 스테로이드
ES2970336T3 (es)	2024-05-28	Intermedios para la síntesis de derivados de ácidos biliares, en particular del ácido obeticólico
ES2733643T3 (es)	2019-12-02	Esteroides 5.beta.-6-alquil-7-hidroxi-3-ona como intermedios para la producción de moduladores FXR de esteroides
EP3221333B1 (fr)	2019-07-24	Stéroïdes 6.alpha.-alkyl-3,7-dione utilisés en tant qu'intermédiaires pour la production de modulateurs de fxr stéroïdiens
BR112018073492B1 (pt)	2025-06-03	Processos de preparo de compostos intermediários na síntese de derivados de ácido biliar com atividade farmacológica
HK40006372A (en)	2020-05-22	Process for the 6,7-alpha-epoxidation of steroid 4,6-dienes
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HK40006371B (en)	2021-08-20	Steroid 6.7.beta.-epoxides as chemical intermediates
HK40006371A (en)	2020-05-22	Steroid 6.7.beta.-epoxides as chemical intermediates
HK40006370B (en)	2022-02-04	Intermediates for the synthesis of bile acid derivatives, in particular of obeticholic acid
HK1244287B (en)	2020-09-18	6.alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal fxr modulators